The importance of NMDA/nitric oxide signalling in mouse olfactory memory

Author:

James, B.

Awarding Body:

University of Cambridge

Current Institution:

University of Cambridge

Date of Award:

2003

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Abstract:

Olfactory learning in rodents is a useful model in which to study general principles of the neural and molecular control of memory in the mammalian brain since it is relatively simple and the neural pathways involved are fairly well defined. The work described in this thesis has investigated the role of the NMDA/nitric oxide signalling pathway in olfactory learning and memory and neural plasticity in the olfactory bulb and piriform cortex using a combination of behavioural, pharmacological, transgenic, neurochemical and neuroanatomical approaches in mice. Initially three different olfactory memory paradigms were developed which were either socially (social habituation/discrimination and social transmission of food preference) or non-socially (conditioned odour discrimination) motivated. These provided robust examples of long-term (³24h) olfactory memory and the conditioned task could also be used for demonstrating reversal learning. Pharmacological experiments revealed that blockade of NMDA-receptors, by MK801, or of nitric oxide release by inhibiting nitric oxide synthase (NOS), by NG-Nitro-L-arginine (L-NARG), impaired formation of a long-term olfactory memory in all three tasks. However, neither olfactory perception nor habituation was affected. Mice with a targeted mutation of the neuronal NOS gene (nNOS-/-) were only impaired on the social habituation/discrimination task and actually showed a more rapid reversal of the conditioned odour discrimination task. Impaired performance of the habituation task could be rescued by treatment with the NO-donor molsidomine. The nNOS-/- mice also failed to show age-related decline of cognitive function in the olfactory conditioning task. The importance of NMDA/NO signalling for neural plasticity in the olfactory system was tested by developing an in vivo neurochemical model of NMDA-evoked potentiation of transmitter release in the olfactory bulb and piriform cortex using microdialysis sampling. This showed that repeated NMDA challenges in the olfactory bulb potentiated evoked noradrenaline, glutamate and GABA release after 4h both in this region and downstream in the piriform cortex.